The insulin-like growth factor-1 receptor (IGF-1R) plays an important role in proliferation, protection against apoptosis and transformation of malignant cells. The IGF-1R is also important for maintaining the malignant phenotype of tumour cells, and is involved in tumour cells developing resistance to the action of anti-cancer drugs. In contrast, the IGF-1R seems not to be an absolute requirement for normal cell growth.
The IGF-1R consists of two identical extracellular alpha-subunits that are responsible for ligand binding, and two identical beta-subunits with a transmembrane domain and an intracellular tyrosine kinase domain. The ligand-receptor interaction results in phosphorylation of tyrosine residues in the tyrosine kinase domain, which spans from amino acid 973 to 1229 of the β-subunit. The major sites for phosphorylation are the clustered tyrosines at position 1131, 1135 and 1136 (LeRoith, D., et al., Endocr Rev 1995 April; 16(2), 143-63). After autophosphorylation, the receptor kinase phosphorylates intracellular proteins, like insulin receptor substrate-1 and Shc, which activate the phosphatidyl inositol-3 kinase and the mitogen-activated protein kinase signalling pathways, respectively.
Based on the pivotal role of IGF-1R in malignant cells, it becomes more and more evident that IGF-1R is a target for cancer therapy (Baserga, R., et al., Endocrine vol. 7, no. 1, 99-102, August 1997). One strategy to block IGF-1R activity is to induce selective inhibition of the IGF-1R tyrosine kinase. However, today there are no selective inhibitors of IGF-1R available.
Drugs containing the cyclolignan podophyllotoxin has been used since centuries, and its anti-cancer properties have attracted particular interest. Undesired side effects of podophyllotoxin have, however, prevented its use as an anti-cancer drug. The mechanism for the cytotoxicity of podophyllotoxin has been attributed to its binding to beta-tubulin, leading to inhibition of microtubule assembly and mitotic arrest. The effect of podophyllotoxin on microtubules required μM concentrations in cell free systems. The trans configuration in the lactone ring of podophyllotoxin has been shown to be required for binding to beta-tubulin. In agreement with this, its stereoisomer picropodophyllin, which has a cis configuration in the lactone ring, has a 50-fold lower affinity for microtubuli and a more than 35-fold higher LD50 in rats. Because of the low affinity for microtubuli of picropodophyllotoxin this compound has attracted little interest. During the last decades the major interest on podophyllotoxin derivatives has concerned etoposide, which is a ethylidene glucoside derivative of 4′-demethyl-epipodophyllotoxin. Etoposide, which has no effect on microtubules, is a DNA topoisomerase II inhibitor, and is currently being used as such in cancer therapy. A 4′-hydroxy instead of a 4′-methoxy group of such cyclolignans is an absolute requirement for them to inhibit topoisomerase II.